title: Nrf2/HO-1 pathway activation by manganese is associated with reactive oxygen species and ubiquitin-proteasome pathway, not MAPKs signaling.
abstract: Manganese has been known to induce neurological disorders similar to Parkinson's disease. One of the features of manganese-induced neurotoxicity is oxidative stress. Accumulating data implicate NF-E2-related factor 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Recent studies suggest that the activation of Nrf2 is induced by manganese in PC12 cells. In the present study, we investigated possible links between reactive oxygen species (ROS), proteasome or mitogen-activated protein kinase (MAPK) signaling and Nrf2/HO-1 activation in manganese-treated PC12 cells. After MnCl(2) treatment, there was an increase in nuclear localization and subsequent binding of Nrf2 to the antioxidant-responsive element (ARE) and upregulation of heme oxygenase-1 (HO-1) protein in PC12 cells. Pretreatment with N-acetyl cysteine, a scavenger of reactive oxygen species, suppressed MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. However, pretreatment with lactacystin, an inhibitor of proteasome activity, enhanced MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. Pretreatment of cells with a pharmacological inhibitor of MAPK (ERK inhibitor PD 98059, P38 inhibitor SB203580 or JNK inhibitor SP600125) did not affect the MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding or subsequent upregulation of HO-1 expression. These results suggest that Nrf2/HO-1 activation by Mn in PC12 cells is associated with ROS and the ubiquitin-proteasome pathway, not MAPK signaling.
authors.affiliation: Department of Occupational and Environmental Health, Fujian Medical University, Fuzhou, 350004, China. fmulhy@163.com
authors.forename: Huangyuan
authors.initials: H
authors.lastname: Li
authors.forename: Siying
authors.initials: S
authors.lastname: Wu
authors.forename: Nian
authors.initials: N
authors.lastname: Shi
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Lian
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008345:Manganese / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D008345:Manganese; D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex